It is well known that women at the onset of menopause, whether such onset occurs naturally or as a result of oophorectomy, develop a number of symptoms including hot flushes, vaginal atrophy, depression, anxiety, and nervousness.sup.1,2 (footnotes listed in Table 11) as well as a decrease in bone density which is defined as osteoporosis if the absolute decrease in bone density reaches a point at which fractures begin to occur..sup.3 As reported in a recent article concerning the post-menopausal patient:.sup.4
"Of all the body systems that are at risk as women age, the skeletal system is one of most vulnerable because it is one of the systems most affected by the declining estrogen production".
Such decline in estrogen production occurs on the onset of menopause and continues throughout a woman's post-menopausal life. The symposium referred to in reference 4 entitled "Current Perspectives in the Management of the Menopausal and Post-Menopausal Patient" (Sept. 25-26, 1986 at Banff, Alberta, Canada) discussed various means of managing menopausal and post-menopausal symptoms, including the use of estrogen replacement therapy to counteract the problems associated with menopause.
Estrogen therapy replacement as noted in the literature.sup.5 is believed to be most effective with an oral dose of conjugated equine estrogens of 0.625 mg/day, with such therapy beginning early in the post-menopausal period. Such treatment has been found effective in the prevention of osteoporosis with reduction in the incidence of vertebral fracture by approximately 90% and of hip fracture by approximately 50%..sup.5
As further noted in the literature.sup.5, low bone mass is an important factor in fracture risk and is related to two factors; namely (1) the amount of bone mass developed as a person matures and (2) accelerated bone loss after the menopause or oophorectomy. It is further noted that the post-menopausal acceleration of bone loss occurs at all skeletal sites and is characterized by loss of trabecular bone which in advanced states, produces significant changes in the architecture of the skeleton, including kyphosis (rounded shoulders and the ribs resting on the iliac crest) with chronic back pain and significant loss of height..sup.5 Trabecular bone is the honeycombed type bone generally found in the interior regions of a bone. Cortical bone is the denser type bone generally found in the outer regions of a bone.
The literature states that the treatment of osteoporosis is difficult in that once a patient has bone loss, no treatment can restore normal bone architecture and even restitution of bone mass will not change the women's body configuration..sup.5 Thus although estrogen replacement therapy instituted during the accelerated bone loss phase of menopause may recoup a small amount of bone mass.sup.6,7,8, such recoupment is believed to be the filling in of the remodeling space that becomes enlarged during this phase of accelerated bone loss..sup.5 In addition, it has been the belief of physicians specializing in this field that estrogen therapy replacement gives better results in terms of maintaining bone mass the earlier it is introduced following the onset of menopause..sup.5
Estrogen therapy has also been demonstrated to reduce cortical bone loss if administered immediately after the onset of menopause..sup.5
It has also been discovered that cessation of therapy causes bone loss to resume, especially trabecular bone..sup.2,5 This acceleration tends to be of the same degree as that seen during the immediate post-menopausal phase. Thus it has been noted that the judicious use of estrogen therapy can reduce the fracture incidence in older women..sup.5 It is however conceded that the particular mechanism of action with regard to estrogen in reducing bone loss is not fully understood..sup.5
A review of the medical literature indicates that no regimen is believed to increase bone density more than a few percentage points after onset of menopause and that at best, use of an estrogen therapy replacement regimen will, for most women, reduce bone loss but will not make any marked improvement in bone density, especially if such a treatment is initiated long after the onset of menopause..sup.2,5
Furthermore, although the medical literature suggests that the use of progesterone in combination with estrogen may reduce the incidence of endometrial cancer.sup.9 associated to some extent with estrogen treatment, no suggestion is made in the medical literature that the combination of estrogen with progesterone will increase bone density beyond the short-term increase in bone mass which may occur during the initial treatment of estrogen..sup.9
A medical literature review of calcium supplementation indicates that the use of calcium alone in post-menopausal women may have limited effect in reducing bone loss, and that there is little data to support calcium supplementation as beneficial to post-menopausal women..sup.2,5,10 One study notes that there is no qualitative difference in bone loss between women with and without calcium supplementation of 1500 mg/day, although there is evidence that the dose of estrogen, if estrogen replacement therapy is prescribed, might be reduced in calcium replete women..sup.10
Another article notes that two recent studies of post-menopausal women did not show any relationship between consumption of dietary calcium over a wide range of intake levels to rates of bone loss from the radius and lumbar spine..sup.11
Applicant has conducted a study with seventy-nine post-menopausal women, the majority of whom showed signs of bone loss. This study has been conducted in conjunction with applicant Walter Leonard's calendar-oriented dispenser (U.S. Pat. No. 4,534,468 and U.S. application Ser. No. 764,945 now U.S. Pat. No. 4,736,849). This latter dispenser discloses a calendar regimen of 0.625 mg of conjugated estrogens for calendar days 1 through 25, 10 mg of medroxyprogesterone acetate for calendar days 16 through 25 and 500 mg calcium carbonate for calendar days 26 through the end of the month. It was believed that this regimen would be beneficial in treating the symptoms associated with menopause, and in view of the medical literature, was also believed to retard bone loss. It was not believed at the start of the study that this regimen would increase bone density in post-menopausal women.
The surprising result after tracking the women in the study for a period of approximately two years is that bone density increased for virtually all patients, and in many cases, bone density increased dramatically. More startling and unusual is the finding that the increase in bone density occurred independent of the patient's age at the onset of the regimen. Such a finding is in direct contradiction of using an estrogen regimen in post-menopausal women, as noted by B. Laurence Riggs of the Mayo Clinic in Rochester, Minn..sup.12 Indeed the data contained herein suggests that the amount of bone density increase is probably independent of the patient's age at the time of regimen onset; a finding which heretofore was believed contraindicated by the medical literature due to the known accelerated bone loss of the trabecular type bone following onset of menopause.
It is furthermore believed that the calendar-oriented nature of this regimen which includes the use of calcium supplementation following the first twenty-five days of the calendar regimen may be beneficial in a two-fold fashion; namely, (1) by increasing patient compliance through use of the calendar-oriented dispenser so that the cyclic starting day of the regimen corresponds to the first day of the calendar month; and (2) that the calcium supplementation may increase the blood level of calcium so as to make this substance more available for bone formation when needed due to the concomitant use of estrogens and progesterone.
Finally it is believed that the specific use of conjugated estrogens in combination with medroxyprogesterone acetate, rather than other forms of the estrogen and progesterone hormone may be therapeutic.
The discovery therefore is this particular drug regimen to increase bone density in post-menopausal women.